1. Field of the Invention
The present invention relates to the field of arthritic disease inhibition or prevention and treatment. In particular, embodiments relate to a composition for the inhibition or prevention and treatment of arthritic disease including an extract of mixed herbs.
2. Description of the Related Art
Arthritis is an autoimmune disease characterized by symptoms such as pain, swelling and stiffness in the joints. The two major forms of arthritis in mammals are inflammatory arthritis such as rheumatoid arthritis (RA), and osteoarthritis (OA), a progressive, degenerative loss of cartilage often secondary to mechanical stress, aging, dysplastic conditions and/or injury. The symptoms of arthritis generally relate to arthrosis of spine, e.g., hallux rigidus, arthrosis psoriaticum, or rheumatic arthritis.
Osteoarthritis manifests similar symptoms to rheumatoid arthritis (RA). In particular, although osteoarthritis begins as a degeneration of articular cartilage, RA begins as an inflammation in synovium. In osteoarthritis, as cartilage deteriorates, a reactive synovitis often develops later on. Conversely, as rheumatoid arthritis erodes cartilage, the secondary osteoarthritis changes the bone and cartilage development. At the final stages of both osteoarthritis and rheumatoid arthritis, suffering joints appear similar to one another.
Osteoarthritis is usually indicated by joint pain which may worsen with exercise and/or an X-ray radiation clearly showing a thinned cartilage. Commonly affected joints are knees, hips, members of the spine, fingers, the base of thumb or the big toe etc. The disease is involved in the destruction of articular cartilage by MMPs (matrix metaloproteinases). MMPs often induce cartilage depletion, which is characterized by degenerative changes in the articular cartilage and caused by the over-production of inflammatory cytokines, e.g., interleukin-1 (IL-1), tumor necrosis factor-α(TNF-α) etc, causing extremely severe pain in joints, tendons, muscles and ligament (Fernandes J. C., The role of cytokines in osteoarthritis pathophysiology, 39, pp 237-246, 2002).
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by the swelling, deformation and destruction of joint, which culminates in severe physical disability. Rheumatic diseases include the diseases occurring at muscles, tendons, joints, bones or sinus, which are generally characterized by an inflammation and/or degeneration. Patients suffering from rheumatoid arthritis may have an imbalance in their immune system, which causes an overproduction of pro-inflammatory cytokines, e.g., TNF-α, IL-1 etc. and a lack of anti-inflammatory cytokines, e.g., IL-10, IL-1, etc. RA is characterized by synovial inflammation, which progresses to a cartilage destruction, bone erosion and subsequent joint deformity. During the inflammation process, polymorphonuclear cells, macrophages and lymphocytes are released from the joint. Activated T-lymphocytes produce cytotoxins and pro-inflammatory cytokines, while macrophages stimulate the release of the prostaglandins and cytotoxins. Vasoactive substances such as histamine, kinins and prostaglandins, are released at the site of inflammation and they cause to an edema, erythema and pain at the region of the inflamed joints.
The main pathology of the affected synovial tissue is a hyperplasia and the sub-intimal infiltration of T and B lymphocytes. Synovial tissue hyperplasia forms in pannus tissue, which irreversibly destroys the cartilage and bone in the affected joint. RA progression is associated with elevated levels of TNF-α and IL-1β produced by macrophages and dendrite cells, an imbalance of Th1/Th2 and over-production of antigen specific immunoglobulins. More specifically, TNF-α and IL-1β directly induce the synthesis of proteolytic enzyme such as matrix metalloproteinase (MMPs) which can break down the extracellular matrix macromolecules. Under normal conditions, the tissue inhibitors of metalloproteinases (TIMPs) bind to MMPs with the ratio of 1:1. The imbalanced ratio of TIMPs to MMPs which is generally caused by the up-regulation of MMPs, results in the continued matrix destruction in RA.
The primary drugs for treating arthritis, which are classified into non-steroidal anti-inflammatory drugs (NSAIDs), include, but are not limited to, aspirin, ibuprofen, naproxen, methotrexate, etc. for alleviating pain and inflammation. Secondary drugs include corticosteroids, slow acting antirheumatic drugs (SAARDs) or disease modifying drugs (DMs), e.g., penicilamine, cyclophosphamide, gold salts, azethioprine, levamisole, etc. The first groups of biological-response modifiers (BRMs) approved by FDA for treatment of RA are TNF-α antagonists which plays a role in binding to its receptor or directly binding to the TNF-α protein. However, the use of DMARDs has been impeded by various disadvantages, for example, the potential of its long-term side effects and toxicity, high cost, hypersensitivity to the medications and infections due to TNF-α blockage, etc.
Degenerative arthritis, one of representative osteo-joint diseases is chronic arthritis. It is difficult to treat the disease with conventionally available anti-inflammatory drugs in clinic. Moreover, the drugs give rise to systemic adverse response such as digestive disorder, gastro-intestinal disorder and renal function disorder. Additionally, the adverse response of the drugs occurs more frequently as the age of patient increases, which causes lots of problems in case of long-term systemic treatment in older people. Therefore, due to the shortcomings of previous systemic treatment therapy, a new drug development having an anti-inflammatory effect as well as a protecting and regenerating effect on cartilage has been urgently needed. The recent theory of drug development has been focused on joint tissue lyase inhibitor, free radical scavenger such as SOD, conservation therapy using by long-term treatment of joint tissue components such as chondroitin or glucosamine etc (Badger A. M. et al., J. Pharmacol. Exp. Ther., 290, pp 587-593, 1999; Choi J. H. et al., Osteoarthritis Cartilage, 10(6), pp 471-478, 2002).
Various biochemical mechanisms, in particular, nitric oxide synthase (NOS) enzyme generating nitric oxide and the other enzymes involved in the synthesis of prostaglandin (PGs) play an important role in the etiological factor of arthritis in vivo. Accordingly, NOS enzyme generating NO from L-Arginine or cyclooxygenase (COX) involved in the synthesis of various prostaglandins have been the main target to block inflammation of arthritis.
According to recent reports, there are several kinds of NOS enzymes, for example, bNOS (brain NOS) existing in brain, nNOS (neuronal NOS) in neuronal system, eNOS (endothelial NOS) in endothelial system etc, which are expressed at regular levels in the human body. A small amount of NO reproduced thereby plays an important role in maintaining of homeostasis such as neuronal transmission or induction of vasodilation etc. whereas an excess amount of NO occurring abruptly by iNOS (induced NOS) induced by various cytokines or external stimulator gives rise to cell toxicity or inflammatory reaction. Chronic inflammation is correlated with the increased activity of iNOS (Chan P. S. et al., Osteoarthritis cartilage, 13(5), pp 387-394, 2005; Appleton I. et al., Adv. Pharmacol., 35, pp 27-28, 1996).
Generally, arthritis occurs due to the late production rate of proteoglycan or collagen in cartilage, which results in loss of cushion function. The articular cartilage consists of water (70˜80%) necessary for lubrication and growth, collagen (10˜15%), proteoglycan (5˜10%) and chondrocyte, wherein proteoglycan has particular structure with core protein attached with several glycosaminoglycan (GAG) (Hardingham et al., J. Rheum(Suppl), 43(2), pp 86-90, 1995).
Lonicerae Japonicae is a flower bud part of Lonicerae spp. belonging to Caprifoliaceae. They taste sweet, are good for detoxifying, and are traditionally used for treating dysentery, pain and swelling. They have been known to have antiulcer, antibacterial, antiviral, antispasmodic, diuretic, anti-inflammatory and analgesic bioactivities. The main components are luteolin, inositol, saponin, tannin, isochlorogenic acid, chlorogenic acid etc (B. S. Chung et al., HyangYakDaeSaJeon, Youngrimsa, pp 939-940, 1989).
Anemarrhena asphodeloides BUNGE belongs to Haemodoraceae. They taste sour and are traditionally used to treat fever, dire thirst, cough and diabetes. They have been known to have hypoglycaemic, anti-pyretic, antiplatelet aggregation, inhibits stress ulcer, sedative, inhibits cAMP phosphodiesterase and Na/K-ATPase, haemolytic, antitumour bioactivities. The main components are various saponins such as timosaponin A-I, timosaponin A-II, timosaponin A-III, timosaponin A-IV, timosaponin B-I, and timosaponin nicotinic acid, magniferin, isomangiferin etc (B. S. Chung et al., HyangYakDaeSaJeon, Youngrimsa, pp 203-204, 1989).
However, the therapeutic effect of an extract of mixed herbs with Lonicera japonica THUNB and Anemarrhena asphodeloides BUNGE on the arthritic disease has not been reported or disclosed in any of above cited literatures, the disclosures of which are incorporated herein by reference.